RATIONALES FOR CANCER-CHEMOTHERAPY WITH PDMP, A SPECIFIC INHIBITOR OFGLUCOSYLCERAMIDE SYNTHASE

A proposed weak point in cancer cells is their need to synthesize nove l or rare glucosphingolipids. It is further proposed that cancer patie nts be treated with a drug that slows the synthesis of glucosylceramid e, the precursor of a large family of glucosphingolipids. Experimental data are furnished for chemotherapeutic and biochemical effects of PD MP, an analog of glucosylceramide and its precursor, ceramide. Promisi ng results were obtained in the treatment of mice carrying Ehrlich asc ites carcinoma cells and rats carrying C6 glioma cells. PDMP was found to be oxidized by cytochrome P-450, but this process could be blocked in vivo with piperonyl butoxide or cimetidine. A high level of blood glucose was found to elevate the size of rat kidneys and their content of UDP-glucose and its product, glucosylceramide. The excessive growt h could be blocked by PDMP, which competes with UDP-glc for binding to glucosylceramide synthase. It is suggested that cancer patients be ma intained at a low glucose level in order to slow the synthesis of gluc osylceramide by tumor cells. Metabolic changes produced by PDMP in cul tured cells, besides a rapid deletion of glucosphingolipids, were accu mulation of the precursors (ceramide and sphingosine), loss of protein kinase C, and accumulation of diacylglycerol. It is suggested that ma ny of the cellular changes produced by PDMP, such as loss of cell bind ing, are owing to existence of glucosylceramide-based ''islands'' floa ting in the outer cell surface; the islands may contain growth factor receptors and adhesion factors. An inhibitor that blocks sphingolipid synthesis, such as cycloserine, may prove to be a useful adjuvant for therapy with PDMP.